We have analyzed the prevalence of indeterminate cytology in patients with thyroid nodules treated at the NIH. We documented that among patients with indeterminate thyroid nodules, the prevalence of thyroid cancer was 26.6%. The cohort of patients with indeterminate thyroid nodules was offered either an active surveillance or surgical treatment. Among patients who were referred for a diagnostic/therapeutic thyroid surgery, thyroid cancer was confirmed by the final pathology in 46% of patients. Our data indicate that surgical treatment could have been avoided in 54% of patients with benign disease. Therefore, we have established an algorithm based on clinical characteristics of the nodule and molecular signature of the fine needle aspiration biopsy samples and circulating free DNA samples. We are planning to test it's accuracy in the current study group as well as in a prospective validation cohort of patients with indeterminate thyroid nodules.